Interleukin-18 (IL-18) is a potent cytokine that plays roles in both innate and acquired immune responses (Nakanishi et al., 2001, Cytokine Growth Factor Rev. 12(1):53-72; Nakanishi et al., 2001, Annu. Rev. Immunol. 19:423-74; Gracie et al., 2003, J. Leukoc. Biol. 73(2):213-224; Reddy, 2004, Curr. Opin. Hematol. 1(6):405-410). IL-18 expression plays a role in a wide variety of pathologic conditions, including autoimmune diseases, bacterial and viral infections, and cancer. Biological activities of IL-18 include induction of interferon-γ (IFN-γ) by, for instance, T cells and splenocytes, enhancement of the killing activity of natural killer cells (NKTs) and helping induce differentiation of naïve CD4+ T cells to type 1 effector T cells (Th1).
IL-18 is synthesized as a biologically-inactive precursor polypeptide. Processing by caspase-1, which cleaves off the leader sequence, yields the biologically-active form (Ghayer et al., 1997, Nature 386:619-623; Gu et al., 1997, Science 275(5297):206-209). Active human IL-18 contains 157 amino acids. IL-18 receptor (IL-18R) components, IL-18Rα and IL-18Rβ, have been identified (Torigoe et al., 1997, J. Biol. Chem. 272:25737-25742; Born et al., 1998, J. Biol. Chem. 2873:29445-29450). A naturally-occurring soluble inhibitor of IL-18, dubbed IL-18BP, has also been identified, which inhibits IL-18 activity by binding to IL-18 (Novick et al., 1999, Immunity 10:127-136).
T cells play a critical role in immune responses. Regulatory T cells (Tregs), are a distinct population of T lymphocytes that have the capacity to dominantly suppress the proliferation of responder T cells in vitro and inhibit autoimmune disease in vivo (Sakaguchi et al., 1995, J. Immunol. 155:1151-1164; Sakaguchi et al., 2006, Curr. Top. Microbiol. Immunol. 305:51-66; Thornton et al., 1998, J. Exp. Med. 188:287-296). Tregs, originally identified as a CD4+CD25′ cell population, are also characterized by the expression of the forkhead family transcription factor FoxP3 (Fontenot et al., 2005, Immunity 22:329-341).
Tumors express tumor-associated antigens, which should result in a immune reaction. However, such tumor-associated antigen specific immune responses have not typically been observed. Tregs have been implicated as major contributors to the ultimate failure of anti-tumor immune responses in humans (Wolf et al., 2006, Mini Rev. Med. Chem. 6(5):509513). For instance, in ovarian cancer, Tregs suppress tumor-specific T cells and high numbers of tumor-associated Tregs are associated with reduced survival time (Curiel et al., 2003, Nat. Med. 9:562-567; Wolf et al., 2005, Clin. Cancer Res. 11:8326-8331; Curiel et al., 2006, Meeting Abstract, Can. Immunity 6 Suppl. 1, p. 20). Furthermore, an increased number of intratumoral effector T cells in ovarian cancer has been associated with a better prognosis (Zhang et al., 2003, N. Engl. J. Med. 348:203-213). A similar observation has been made with respect to colorectal cancer (Pages et al., 2005, N. Engl. J. Med. 353:2654-2666). Lung tumors have been shown to have a high number of Tregs, and the evidence suggests that Tregs selectively inhibit the host immune response and may thereby contribute to cancer progression (Woo et al., 2002, J. Immunol. 168:4272-4276). Tregs have also been shown to be elevated in tumor samples from glioblastoma multiforme patients (Andaloussi et al., 2006, Neuro-oncol. 8:234-243).
Administration of DAB389IL-2, a recombinant IL-2 diphtheria toxin conjugate, to eliminate Tregs from peripheral blood of metastatic renal cell carcinoma patients prior to vaccination with tumor RNA-transfected dendritic cells resulted in enhanced stimulation of tumor-specific T cells (Dannull et al., 2005, J. Clin. Inves. 115:3623:3633). Disadvantageously, DAB389IL-2 removes activated T cells and therefore, cannot be used following vaccination. Fludarabine has been shown to either eliminate or block Tregs in chronic lymphocytic leukemia patients (Beyer et al., 2005, Blood 106:2018-2025). Disadvantageously, fludarabine can cause suppression of bone marrow cells and neurotoxicity.
Tregs also play a role in some viral and parasitic infections. For instance, an overabundance of Tregs and resultant immune suppression have been detected in retroviral infections (Iwashiro et al., 2001, PNAS 98:9226-9230). Immune suppression by Tregs has also been found in Leishmania and malaria mouse models (Belkaid et al., Nature 420:502; Hisaeda et al., 2004, Nat. Med. 10:29). In a filarial-infected mouse model, reduction in the number of Tregs by antibody therapy resulted in a dramatic reduction in parasite numbers (Taylor et al., 2005, J. Immunol. 174:4924-4933).
Thus, it is clear there is a need in the art for a new method for inhibiting or reducing Tregs in the treatment of cancer and other diseases involving Tregs. The present invention satisfies this need.